tbuckley/cabot-search huggingface dataset:
Radiotherapy-Induced Neurocognitive Impairment Is Driven by Heightened Apoptotic Priming in Early Life and Prevented by Blocking BAX
Authors: Rumani Singh, Stacey Yu, Marwa Osman, Zintis Inde, Cameron Fraser, Abigail H. Cleveland, Nicole Almanzar, Chuan Bian Lim, Gaurav N. Joshi, Johan Spetz, Xingping Qin, Sneh M. Toprani, Zachary Nagel, Matthew C. Hocking, Robert A. Cormack, Torunn I. Yock, Jeffrey W. Miller, Zhi-Min Yuan, Timothy Gershon, Kristopher A. Sarosiek
Journal: Cancer Research (2023)

Abstract Although external beam radiotherapy (xRT) is commonly used to treat central nervous system (CNS) tumors in patients of all ages, young children treated with xRT frequently experience life-altering and dose-limiting neurocognitive impairment (NI) while adults do not. The lack of understanding of mechanisms responsible for these differences has impeded the development of neuroprotective treatments. Using a newly developed mouse model of xRT-induced NI, we found that neurocognitive function is impaired by ionizing radiation in a dose- and age-dependent manner, with the youngest animals being most affected. Histologic analysis revealed xRT-driven neuronal degeneration and cell death in neurogenic brain regions in young animals but not adults. BH3 profiling showed that neural stem and progenitor cells, neurons, and astrocytes in young mice are highly primed for apoptosis, rendering them hypersensitive to genotoxic damage. Analysis of single-cell RNA sequencing data revealed that neural cell vulnerability stems from heightened expression of proapoptotic genes including BAX, which is associated with developmental and mitogenic signaling by MYC. xRT induced apoptosis in primed neural cells by triggering a p53- and PUMA-initiated, proapoptotic feedback loop requiring cleavage of BID and culminating in BAX oligomerization and caspase activation. Notably, loss of BAX protected against apoptosis induced by proapoptotic signaling in vitro and prevented xRT-induced apoptosis in neural cells in vivo as well as neurocognitive sequelae. On the basis of these findings, preventing xRT-induced apoptosis specifically in immature neural cells by blocking BAX, BIM, or BID via direct or upstream mechanisms is expected to ameliorate NI in pediatric patients with CNS tumor. Significance: Age- and differentiation-dependent apoptotic priming plays a pivotal role in driving radiotherapy-induced neurocognitive impairment and can be targeted for neuroprotection in pediatric patients.
Proteomics analysis of plasma from middle-aged adults identifies protein markers of dementia risk in later life
Authors: Keenan A. Walker, Jingsha Chen, Liu Shi, Yunju Yang, Myriam Fornage, Linda Zhou, Pascal Schlosser, Aditya Surapaneni, Morgan E. Grams, Michael R. Duggan, Zhongsheng Peng, Gabriela T. Gomez, Adrienne Tin, Ron C. Hoogeveen, Kevin J. Sullivan, Peter Ganz, Joni V. Lindbohm, Mika Kivimaki, Alejo J. Nevado-Holgado, Noel Buckley, Rebecca F. Gottesman, Thomas H. Mosley, Eric Boerwinkle, Christie M. Ballantyne, Josef Coresh
Journal: Science Translational Medicine (2023)

A diverse set of biological processes have been implicated in the pathophysiology of Alzheimer's disease (AD) and related dementias. However, there is limited understanding of the peripheral biological mechanisms relevant in the earliest phases of the disease. Here, we used a large-scale proteomics platform to examine the association of 4877 plasma proteins with 25-year dementia risk in 10,981 middle-aged adults. We found 32 dementia-associated plasma proteins that were involved in proteostasis, immunity, synaptic function, and extracellular matrix organization. We then replicated the association between 15 of these proteins and clinically relevant neurocognitive outcomes in two independent cohorts. We demonstrated that 12 of these 32 dementia-associated proteins were associated with cerebrospinal fluid (CSF) biomarkers of AD, neurodegeneration, or neuroinflammation. We found that eight of these candidate protein markers were abnormally expressed in human postmortem brain tissue from patients with AD, although some of the proteins that were most strongly associated with dementia risk, such as GDF15, were not detected in these brain tissue samples. Using network analyses, we found a protein signature for dementia risk that was characterized by dysregulation of specific immune and proteostasis/autophagy pathways in adults in midlife ~20 years before dementia onset, as well as abnormal coagulation and complement signaling ~10 years before dementia onset. Bidirectional two-sample Mendelian randomization genetically validated nine of our candidate proteins as markers of AD in midlife and inferred causality of SERPINA3 in AD pathogenesis. Last, we prioritized a set of candidate markers for AD and dementia risk prediction in midlife.
Understanding how health interventions or exposures produce their effects using mediation analysis
Authors: Aidan G Cashin, James H McAuley, Tyler J VanderWeele, Hopin Lee
Journal: BMJ (2023)

Mediation analysis is a method that quantifies how health exposures, such as medical interventions, change patient outcomes. Evidence that is generated from mediation analyses is important for intervention development and clinical and policy decision making. Mediation analysis has many applications that require specific and careful consideration for design, conduct, analysis, and interpretation. This article outlines motivations, effect types, causal assumptions, estimation, and reporting guidance for mediation analysis studies that aim to improve their conduct, interpretation, and implementation.
Influenza versus other respiratory viruses – assessing severity among hospitalised children, Belgium, 2011 to 2020
Authors: Natalie Fischer, Sarah Moreels, Nicolas Dauby, Marijke Reynders, Evelyn Petit, Michèle Gérard, Patrick Lacor, Siel Daelemans, Bénédicte Lissoir, Xavier Holemans, Koen Magerman, Door Jouck, Marc Bourgeois, Bénédicte Delaere, Sophie Quoilin, Steven Van Gucht, Isabelle Thomas, Nathalie Bossuyt, Cyril Barbezange
Journal: Eurosurveillance (2023)

BackgroundKnowledge on the burden attributed to influenza viruses vs other respiratory viruses in children hospitalised with severe acute respiratory infections (SARI) in Belgium is limited.AimThis observational study aimed at describing the epidemiology and assessing risk factors for severe disease.MethodsWe retrospectively analysed data from routine national sentinel SARI surveillance in Belgium. Respiratory specimens collected during winter seasons 2011 to 2020 were tested by multiplex real-time quantitative PCR (RT-qPCR) for influenza and other respiratory viruses. Demographic data and risk factors were collected through questionnaires. Patients were followed-up for complications or death during hospital stay. Analysis focused on children younger than 15 years. Binomial logistic regression was used to identify risk factors for severe disease in relation to infection status.ResultsDuring the winter seasons 2011 to 2020, 2,944 specimens met the study case definition. Complications were more common in children with underlying risk factors, especially asthma (adjusted risk ratio (aRR): 1.87; 95% confidence interval (CI): 1.46-2.30) and chronic respiratory disease (aRR: 1.88; 95% CI: 1.44-2.32), regardless of infection status and age. Children infected with non-influenza respiratory viruses had a 32% higher risk of complications (aRR: 1.32; 95% CI: 1.06-1.66) compared with children with influenza only.ConclusionMulti-virus testing in children with SARI allows a more accurate assessment of the risk of complications and attribution of burden to respiratory viruses beyond influenza. Children with asthma and respiratory disease should be prioritised for clinical care, regardless of their virological test result and age, and targeted for prevention campaigns.
Surveillance of athlete mental health symptoms and disorders: a supplement to the International Olympic Committee’s consensus statement on injury and illness surveillance
Authors: Margo Mountjoy, Astrid Junge, Abhinav Bindra, C Blauwet, Richard Budgett, Alan Currie, Lars Engebretsen, Brian Hainline, David McDuff, Rosemary Purcell, Margot Putukian, Claudia L Reardon, Torbjørn Soligard, Vincent Gouttebarge
Journal: British Journal of Sports Medicine (2023)

In 2019, the International Olympic Committee (IOC) published a consensus statement outlining the principles for recording and reporting injury and illness in elite sport. The authors encouraged sport federations to adapt the framework to their sport-specific context. Since this publication, several sports have published extensions to the IOC consensus statement.In response to a paucity of epidemiological data on athlete mental health, the IOC mental health working group adapted the IOC consensus statement on injury and illness surveillance to improve the capturing of athlete mental health data. In addition to the members of the working group, other experts and athlete representatives joined the project team to address gaps in expertise, and to add stakeholder perspective, respectively. Following an in-person meeting, the authors worked remotely, applying the scientific literature on athlete mental health to the IOC injury and illness surveillance framework. A virtual meeting was held to reach consensus on final recommendations.Practical outcomes based on the analysis of the scientific literature are provided with respect to surveillance design, data collection and storage, data analysis and reporting of athlete mental health data. Mental health-specific report forms for athlete and health professional utilisation are included for both longitudinal and event-specific surveillance.Ultimately, this publication should encourage the standardisation of surveillance methodology for mental health symptoms and disorders among athletes, which will improve consistency in study designs, thus facilitating the pooling of data and comparison across studies. The goal is to encourage systematic surveillance of athlete mental health.
A Biomimetic Nanogel System Restores Macrophage Phagocytosis for Magnetic Resonance Imaging‐Guided Synergistic Chemoimmunotherapy of Breast Cancer
Authors: Lulu Li, Yue Gao, Yiming Zhang, Rui Yang, Zhijun Ouyang, Rui Guo, Hongwei Yu, Xiangyang Shi, Xueyan Cao
Journal: Advanced Healthcare Materials (2023)

Novel strategies to facilitate tumor-specific drug delivery and restore immune attacks remain to be developed to overcome the current limitations of chemotherapy. Herein, a cancer cell membrane (CM)-camouflaged and ultrasmall iron oxide nanoparticles (USIO NPs)-loaded polyethylenimine nanogel (NG) system is reported to co-deliver docetaxel (DTX) and CD47 siRNA (siCD47). The prepared co-delivery system exhibits good colloidal stability, biocompatibility, and r1 relaxivity (1.35 mM-1 s-1 ) and enables redox-responsive release of the loaded DTX in the tumor microenvironment. The NG system realizes homologous targeting delivery of DTX and siCD47 to murine breast cancer cells (4T1 cells) for efficient chemotherapy and gene silencing; thus, inducing immunogenic cell death (ICD) and restoring macrophage phagocytic effect through downregulation of "don't eat me" signals on cancer cells. Likewise, the co-delivery system can also act on macrophages to promote their M1 polarization, which can be combined with DTX-mediated ICD and antibody-mediated immune checkpoint blockade to generate effector T cells for robust chemoimmunotherapy. Further, the USIO NPs-incorporated NG system also allows for magnetic resonance imaging of tumors. The developed biomimetic NG system acting on both cancer cells and macrophages holds a promising potential for macrophage phagocytosis-restored chemoimmunotherapy.
Mind and skin: Exploring the links between inflammation, sleep disturbance and neurocognitive function in patients with atopic dermatitis
Authors: Shona Cameron, Ali Donnelly, Conor Broderick, Tomoki Arichi, Ullrich Bartsch, Paola Dazzan, Jesper Elberling, Emma Godfrey, Paul Gringras, Lauren C. Heathcote, Desaline Joseph, Tobias C. Wood, Carmine Pariante, Katya Rubia, Carsten Flohr
Journal: Allergy (2023)

Abstract Atopic dermatitis (AD) is a chronic, pruritic and inflammatory, dry skin condition with many known comorbidities. These include airway disease, food allergies, atopic eye disease and autoimmune conditions. Furthermore, there is often significant sleep disturbance as well as increased psychological distress and mental health problems. Severe AD therefore often has a significant impact on the quality of life of both patients and their families. In this review we discuss recent findings on the putative links between AD, its association with itch, sleep disturbance and neuropsychiatric morbidity, including the role of inflammation in these conditions. Itch was thought to predominantly drive sleep disruption in AD. We now understand changes in sleep influence immune cell distribution and the associated inflammatory cytokines, which suggests a bidirectional relationship between AD and sleep. We also increasingly recognize inflammation as a key driver in psychological symptoms and disorders. The link between cutaneous, systemic and possible brain inflammation could at least in part be driven by the sleep deprivation and itch‐driven neuronal proliferation seen in AD.
Mechanism and application of β‐adrenoceptor blockers in soft tissue wound healing
Authors: Shasha Jia, Xueya Wang, Guowei Wang, Xiaojing Wang
Journal: Medicinal Research Reviews (2023)

Soft tissue damage stimulates sympathetic nerves to release large amounts of catecholamine hormones which bind to β-adrenergic receptors (β-ARs) on the cell membrane surface. It activates the downstream effector molecules and impairs soft tissue wound healing. β-blockers specifically inhibit β-ARs activation in acute/chronic skin lesions and ulcerative hemangiomas. They also accelerate soft tissue wound healing by shortening the duration of inflammation, speeding keratinocyte migration and reepithelialization, promoting wound contraction and angiogenesis, and inhibiting bacterial virulence effects. In addition, β-blockers shorten wound healing periods in patients with severe thermal damage by reducing the hypermetabolic response. While β-blockers promote/inhibit corneal epithelial cell regeneration and restores limbal stem/progenitor cells function, it could well accelerate/delay corneal wound healing. Given these meaningful effects, a growing number of studies are focused on examining the efficacy and safety of β-blockers in soft tissue wound repair, including acute and chronic wounds, severe thermal damage, ulcerated infantile hemangioma, corneal wounds, and other soft tissue disorders. However, an intensive investigation on their acting mechanisms is imperatively needed. The purpose of this article is to summerize the roles of β-blockers in soft tissue wound healing and explore their clinical applications.
The Aging Biomarker Consortium represents a new era for aging research in China
Authors: Jie Ren, Moshi Song, Weiqi Zhang, Jian-Ping Cai, Feng Cao, Zhongwei Cao, Piu Chan, Chang Chen, Guobing Chen, Hou-Zao Chen, Jun Chen, Xiao-Chun Chen, Weimin Ci, Bi-Sen Ding, Qiurong Ding, Feng Gao, Shaorong Gao, Jing-Dong J. Han, Qi-Yang He, Kai Huang, Zhenyu Ju, Qing-Peng Kong, Ji Li, Jian Li, Jingyi Li, Xin Li, Baohua Liu, Feng Liu, Jun-Ping Liu, Lin Liu, Qiang Liu, Qiang Liu, Xingguo Liu, Yong Liu, Xianghang Luo, Shuai Ma, Xinran Ma, Zhiyong Mao, Jing Nie, Yaojin Peng, Jing Qu, Ruibao Ren, Weihong Song, Zhou Songyang, Liang Sun, Yi Eve Sun, Yu Sun, Mei Tian, Xiao-Li Tian, Ye Tian, Jianwei Wang, Shusen Wang, Si Wang, Wengong Wang, Xia Wang, Xiaoning Wang, Yan-Jiang Wang, Yunfang Wang, Catherine C. L. Wong, Andy Peng Xiang, Yichuan Xiao, Zhi-Xiong Xiao, Zhengwei Xie, Wei Xiong, Daichao Xu, Ze Yang, Jing Ye, Wei Yu, Rui Yue, Cuntai Zhang, Hongbo Zhang, Liang Zhang, Xinchao Zhang, Yong Zhang, Yun-Wu Zhang, Zhuohua Zhang, Tongbiao Zhao, Yuzheng Zhao, Zhongjun Zhou, Dahai Zhu, Weiguo Zou, Gang Pei, Guang-Hui Liu
Journal: Nature Medicine (2023)
A Core–Shell Nanoreinforced Ion‐Conductive Implantable Hydrogel Bioelectronic Patch with High Sensitivity and Bioactivity for Real‐Time Synchronous Heart Monitoring and Repairing
Authors: Si Shen, Jie Zhang, Yanni Han, Chunyi Pu, Qixiang Duan, Jianxing Huang, Bing Yan, Xintong You, Rurong Lin, Xiaoxi Shen, Xiaozhong Qiu, Honghao Hou
Journal: Advanced Healthcare Materials (2023)

To achieve synchronous repair and real-time monitoring the infarcted myocardium based on an integrated ion-conductive hydrogel patch is challenging yet intriguing. Herein, a novel synthetic strategy is reported based on core-shell-structured curcumin-nanocomposite-reinforced ion-conductive hydrogel for synchronous heart electrophysiological signal monitoring and infarcted heart repair. The nanoreinforcement and multisite cross-linking of bioactive curcumin nanoparticles enable well elasticity with negligible hysteresis, implantability, ultrahigh mechanoelectrical sensitivity (37 ms), and reliable sensing capacity (over 3000 cycles) for the nanoreinforced hydrogel. Results of in vitro and in vivo experiments demonstrate that such solely physical microenvironment of electrophysiological and biomechanical characteristics combining with the role of bioactive curcumin exert the synchronous benefit of regulating inflammatory microenvironment, promoting angiogenesis, and reducing myocardial fibrosis for effective myocardial infarction (MI) repair. Especially, the hydrogel sensors offer the access for achieving accurate acquisition of cardiac signals, thus monitoring the whole MI healing process. This novel bioactive and electrophysiological-sensing ion-conductive hydrogel cardiac patch highlights a versatile strategy promising for synchronous integration of in vivo real-time monitoring the MI status and excellent MI repair performance.
Systematic single amino acid affinity tuning of CD229 CAR T cells retains efficacy against multiple myeloma and eliminates on-target off-tumor toxicity
Authors: Erica R. Vander Mause, Jillian M. Baker, Kenneth A. Dietze, Sabarinath V. Radhakrishnan, Thierry Iraguha, Destiny Omili, Patricia Davis, Sadie L. Chidester, Katarzyna Modzelewska, Jens Panse, James E. Marvin, Michael L. Olson, Mary Steinbach, David P. Ng, Carol S. Lim, Djordje Atanackovic, Tim Luetkens
Journal: Science Translational Medicine (2023)

T cells expressing chimeric antigen receptors (CARs) have shown remarkable therapeutic activity against different types of cancer. However, the wider use of CAR T cells has been hindered by the potential for life-threatening toxicities due to on-target off-tumor killing of cells expressing low amounts of the target antigen. CD229, a signaling lymphocyte-activation molecule (SLAM) family member, has previously been identified as a target for CAR T cell–mediated treatment of multiple myeloma (MM) due to its high expression on the surfaces of MM cells. CD229 CAR T cells have shown effective clearance of MM cells in vitro and in vivo. However, healthy lymphocytes also express CD229, albeit at lower amounts than MM cells, causing their unintended targeting by CD229 CAR T cells. To increase the selectivity of CD229 CAR T cells for MM cells, we used a single amino acid substitution approach of the CAR binding domain to reduce CAR affinity. To identify CARs with increased selectivity, we screened variant binding domains using solid-phase binding assays and biolayer interferometry and determined the cytotoxic activity of variant CAR T cells against MM cells and healthy lymphocytes. We identified a CD229 CAR binding domain with micromolar affinity that, when combined with overexpression of c-Jun, confers antitumor activity comparable to parental CD229 CAR T cells but lacks the parental cells’ cytotoxic activity toward healthy lymphocytes in vitro and in vivo. The results represent a promising strategy to improve the efficacy and safety of CAR T cell therapy that requires clinical validation.
Targeting the Siglec–sialic acid axis promotes antitumor immune responses in preclinical models of glioblastoma
Authors: Philip Schmassmann, Julien Roux, Alicia Buck, Nazanin Tatari, Sabrina Hogan, Jinyu Wang, Natalia Rodrigues Mantuano, Ronja Wieboldt, Sohyon Lee, Berend Snijder, Deniz Kaymak, Tomás A. Martins, Marie-Françoise Ritz, Tala Shekarian, Marta McDaid, Michael Weller, Tobias Weiss, Heinz Läubli, Gregor Hutter
Journal: Science Translational Medicine (2023)

Glioblastoma (GBM) is the most aggressive form of primary brain tumor, for which effective therapies are urgently needed. Cancer cells are capable of evading clearance by phagocytes such as microglia- and monocyte-derived cells through engaging tolerogenic programs. Here, we found that high expression of sialic acid–binding immunoglobulin-like lectin 9 (Siglec-9) correlates with reduced survival in patients with GBM. Using microglia- and monocyte-derived cell-specific knockouts of Siglec-E, the murine functional homolog of Siglec-9, together with single-cell RNA sequencing, we demonstrated that Siglec-E inhibits phagocytosis by these cells, thereby promoting immune evasion. Loss of Siglec-E on monocyte-derived cells further enhanced antigen cross-presentation and production of pro-inflammatory cytokines, which resulted in more efficient T cell priming. This bridging of innate and adaptive responses delayed tumor growth and resulted in prolonged survival in murine models of GBM. Furthermore, we showed the combinatorial activity of Siglec-E blockade and other immunotherapies demonstrating the potential for targeting Siglec-9 as a treatment for patients with GBM.